The present invention relates to an improved method for the preparation of 2-chlorosulfinyl azetidine-4-ones (II) from penicillin sulfoxide esters (I). In particular, it relates to an improvement in the first step of a two-step process for converting penicillin sulfoxide esters (I) via 2-chlorosulfinyl azetidine-4-one intermediates (II) to 3-exomethylene cepham sulfoxide esters (III). ##STR1##
According to this invention, a sulfoxide ester (I) is reacted with an N-chlorohalogenating agent in the presence of a strongly basic ion exchange resin cross-linked with styrene-divinyl benzene copolymer to provide the corresponding 2-chlorosulfinyl azetidine-4-one (II). The improvement comprises the use of an ion exchange resin incorporating a quaternary ammonium functionality which removes hydrogen chloride formed in the reaction medium, thus preventing the formation of degradation products and hence giving overall higher yields. Commercial availability of the ion-exchange resins, their complete and easy removal from the reaction medium by simple filtration and their regeneration make this process commercially economical.
The 2-chlorosulfinyl azetidine-4-one compounds (II) are valuable intermediates in the preparation of 3-exomethylene cepham-4-carboxylic acid ester sulfoxides (III) which in turn are used in the manufacture of clinically useful antibacterial agents such as Cefaclor, Cefroxadine etc. These intermediate compounds (II) are prepared by the reaction of corresponding penicillin sulfoxide esters (I) with an N-chlorohalogenating agent such as N-chlorosuccinimide or N-chlorophthalimide in an inert organic solvent at 75.degree.-140.degree. C.
U.S. Pat. No. 4,052,387 (Oct. 4, 1977) and U.S. Pat. No. 4,081,440 (Mar. 28, 1978) by Kukolja describe a process for the preparation of 2-chlorosulfinyl azetidine-4-one (II) by treatment of the corresponding penicillin sulfoxide ester (I) with an N-chlorohalogenating agent in an inert organic solvent in the presence or absence of a non-alkaline acid scavenger such as propylene oxide, butylene oxide and the like to remove any hydrogen chloride formed in the reaction. Cyclization of the intermediate (II) with a Friedel-Crafts catalyst affords the corresponding 3-exomethylene cepham-4-sulfoxide ester (III) in an overall yield of 25-40% (with the exception of example 8 in U.S. Pat. No. 4,052,387).
Further, in U.S. Pat. No. 4,165,315 (Aug. 21, 1979), Kukolja describes a method similar to that of U.S. Pat. Nos. 4,052,387 and 4,081,440 for the preparation of 2-chlorosulfinyl azetidine-4-one (II) by using a non-alkaline acid scavenger such as propylene oxide which on cyclization with stannic chloride gives the exomethylene compound III in a very low yield (9-34%).
The method described in the above patents does not provide an economical, commercially viable process. When the reaction scale is increased beyond typical research laboratory quantities, for example in those instances where 50 grams or more of the penicillin sulfoxide ester has been used as a starting material, the results are poor.
In U.S. Pat. No. 4,075,203 (Feb. 21, 1978) and U.S. Pat. No. 4,165,316 (Aug. 27, 1979) Chou described an improved process for the preparation of 2-chlorosulfinyl azetidine-4-one intermediate (II) by carrying out the reaction of penicillin sulfoxide ester (I) with an N-chlorohalogenating agent in the presence of an alkylene oxide in combination with calcium oxide as a hydrogen chloride acceptor. The intermediate (II), on cyclization with a Lewis acid, affords 3-exomethylene cepham ester (III) with an overall yield varying between 32-59%.
Further improvement is reported in U.S. Pat. No. 4,289,695 (Sept. 15, 1981) by Chou, wherein the use of a weakly basic, organic solvent insoluble poly-(4-vinyl pyridine) polymer cross-linked with divinyl benzene as a hydrogen chloride binding agent has been used in the chlorinating step to give 2-chlorosulfinyl azetidine-4-one (II) which on cyclization with a Lewis acid gives the corresponding 3-exomethylene cepham sulfoxide ester (III) in an overall yield of 10-76%.